1. Field of the Invention
The present invention is related to the delivery of drugs from implantable medical devices. More specifically, the present invention relates to formulations of hydrophobic anti-oxidant, anti-inflammatory and anti-restenotic agents and vascular stents and balloons having an oil-based coating suitable for delivering anti-oxidant, anti-inflammatory and anti-restenotic agents.
2. Description of the Related Art
Over one million angioplasty procedures are performed annually with about 80% of these involving the placement of a metal stent. Although, both balloon angioplasty and stenting of clogged coronary arteries result in an immediate clearing of the obstruction and resumption of coronary blood flow, within six months 20-50% of the arteries require revascularization. The mechanism of restenosis has been found to be related to both mechanical stretch injury and remodeling of the artery wall due to smooth muscle cell proliferation into the lumen called neointimal hyperplasia (NIH). In both instances, the cause of the reduced artery flow is actually induced by balloon angioplasty and/or placement of the stent. Originally, balloon angioplasty by itself was responsible for stretch injury and recoil that lead to as much as 50% restenosis in susceptible patients. To counter the effects of recoil and prop the artery open further, the practice of deploying a metal stent was introduced and the values of restenosis have dropped to between 20-30% depending on the patient population.
Drugs such as rapamycin and paclitaxel have been demonstrated to reduce NIH and further reduce the rate of stenosis when coated on a metal stent. These drugs act to prevent smooth muscle cell (SMC) proliferation which is a direct consequence of the damage done to the internal elastica and the medial layers during the deployment of the balloon and/or stent. A new agent C6-ceramide (CERACOR™)—a water insoluble lipid, has also been demonstrated to inhibit SMC proliferation in both in vitro cell culture and in vivo animal studies (rabbit carotid model and pig coronary) (Charles et al. 2000 Circ Res 87:282-288). C6-ceramide has been shown to initiate activity within 15 minutes of application of a single dose from an angioplasty balloon.
Initial experiments with C6-ceramide coated on the balloon from a dimethylsulfoxide/ethanol solution revealed that the physical form of the drug changes with time. Initially, the deposited lipid form a translucent film, but within an hour or so the deposited material slowly transforms to a white crystallite appearance. The deposition uniformity as measured by microscopy is spotty across the balloon surface. After several days, the white powder continues to transform until it flakes off the balloon and is no longer believed to be in an available state. Decreased availability may be described as the dissolution/deaggregation time of the solid relative to deposition and diffusion within the artery, which prevents it from exerting its effect. Currently, to study the effect of C6-ceramide in animal models, the DMSO/ethanol formulation containing C6-ceramide is coated onto the balloon just prior to insertion into the artery. The role of the solvent is to keep the lipid material in an available film-like state sufficient for it to be rapidly deposited and absorbed quickly in the artery, where it is shown to exert an effect within 15 minutes. However, organic solvents, in which the drug is very soluble, tend to evaporate rapidly and the solvents may also penetrate and affect the balloon performance. Alternative solvents and formulations are needed that permit the drug to remain in a dissolved state yet remain physically stable without changing with time.